CN105949173B - A kind of preparation method of aspartic acid laumosaren - Google Patents
A kind of preparation method of aspartic acid laumosaren Download PDFInfo
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- CN105949173B CN105949173B CN201610354661.3A CN201610354661A CN105949173B CN 105949173 B CN105949173 B CN 105949173B CN 201610354661 A CN201610354661 A CN 201610354661A CN 105949173 B CN105949173 B CN 105949173B
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- aspartic acid
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- lomefloxacin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The present invention relates to a kind of preparation methods of anti-infectious agent,More particularly to a kind of preparation method of aspartic acid laumosaren,The preparation process of the preparation method is by lomefloxacin hydrochloride and water,Alkaline aqueous solution proportionally carries out neutralization reaction,Obtain Lomefloxacin base,By the Lomefloxacin base and L L-aminobutanedioic acids of neutralization reaction generation,Water proportionally carries out salt-forming reaction,Obtain aspartic acid laumosaren wet product,By Lomefloxacin base and L L-aminobutanedioic acids,The mother liquor of purified water salt-forming reaction is refined,Obtain aspartic acid laumosaren wet product,Acquisition finished product finally is dried in aspartic acid laumosaren wet product,Generally,The present invention carries out reaction and effectively reduces production cost in water,Improve reaction speed,Improve the security in production process,Improve Business Economic Benefit,There is high practical value.
Description
Technical field
The present invention relates to a kind of preparation methods of anti-infectious agent, and in particular to a kind of preparation side of aspartic acid laumosaren
Method.
Background technology
Lomefloxacin (Lomefloxacin) is the 3rd generation carbostyril family antibacterial drugs, to including the gram of Pseudomonas aeruginosa
Negative bacterium and positive bacteria have broad-spectrum antibacterial action, at present, respiratory tract caused by being widely used in sensitive bacterial, urogenital tract,
The treatments such as biliary tract, enteron aisle, skin soft-tissue infection and tympanitis, nasosinusitis, the common its esters of clinic.L-aminobutanedioic acid Lome is husky
Star (LomefloxacinAspartate) is its acylate, right for relatively common inorganic acid salt such as lomefloxacin hydrochloride
The irritation smaller of human body, the tolerance of patient are more preferable.But salt-forming reaction of the prior art is anti-in ethanol water
Should, and ethyl alcohol cost is higher, therefore it is imperative to improve aspartic acid laumosaren preparation process.
The content of the invention
It is an object of the invention to overcome deficiency of the prior art and low, the production method letter that provides a kind of production cost
It is single, a kind of preparation method for aspartic acid laumosaren that finished product is stablized.
The technical proposal of the invention is realized in this way：A, neutralization reaction：Weigh lomefloxacin hydrochloride and alkaline aqueous solution
Middle OH-The molar ratio of content is 1:1.0 ~ 1.2 lomefloxacin hydrochloride and alkaline aqueous solution is spare, weighs lomefloxacin hydrochloride
The water that 400 ~ 800 times of molal quantity is added in reaction kettle, and addition weighs spare lomefloxacin hydrochloride and is stirred, and heats to
60-90 DEG C makes lomefloxacin hydrochloride be dissolved completely in water, starts that alkaline aqueous solution is slowly added dropwise, adjust the pH value of solution for 6 ~
8, heat preservation carry out reaction 1 ~ 2 it is small when, reaction solution is carried out after the completion of reaction to be cooled to room temperature；B, centrifugal drying material：By neutralization reaction
Liquid carries out centrifugal drying material, and is eluted using water into filtrate without chlorion, obtains Lomefloxacin base wet product；C, it is anti-into salt
It should：According to 1:1:50 ~ 70 molar ratio weighs Lomefloxacin base, L-ASPARTIC ACID, water respectively, and the water weighed, Lome is husky
Star base, L-ASPARTIC ACID are sequentially added in retort, are stirred, and heating makes retort be warming up to 50 ~ 95 DEG C, and heat preservation carries out
When reaction 2 ~ 4 is small, aspartic acid laumosaren crude product solution is obtained；D, decolorization filtering：It is molten to aspartic acid laumosaren crude product
Medicinal carbon is added in liquid, is stirred absorption 30 minutes, heat filtering press filtration filtrate enters in crystallizing tank；E, crystallization centrifugation：
It is stirred, after being naturally cooling to 40 ~ 60 DEG C, cooling water is led in crystallizing tank makes temperature be reduced to less than 30 DEG C, progress blowing
Centrifugation, elutes filter cake using ethanol water, obtains aspartic acid laumosaren wet product and mother liquor；F, mother liquor refines：
Mother liquor is added in treatment tank, stirring is opened, after being evacuated to -0.1 ~ -0.07MPa, is heated to 50 ~ 90 DEG C and is depressurized
It is concentrated into when mother liquor volume reduces about 2/3 and stops concentration, release vacuum addition medicinal carbon, be warming up to 60 ~ 90 DEG C and protected
Temperature stirring 30 minutes, heat filtering press filtration are crystallized, blowing centrifugation, filter cake are eluted with ethanol water into crystallizing tank,
Obtain aspartic acid laumosaren wet product；G, dries pulverizing is packed：The aspartic acid laumosaren that step e and step f is obtained
Wet product is packed into baking pan, and baking pan is top-down to be encased on drying vehicle, and drying vehicle is pushed into heated-air circulation oven and is dried,
80 ~ 88 DEG C of oven temperature is controlled, is dried to material moisture≤3.5%, carries out cooling discharge, crush, weigh as needed,
It dispenses into complex pocket.
The alkaline aqueous solution is ammonium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, the aqueous solution of sodium acid carbonate.
Alcoholic strength >=50% in the ethanol water.
The water is water of the drinking water through hyoscine made from the way of distillation, ion-exchange, hyperfiltration.
The beneficial effect comprise that：Lomefloxacin base and L-ASPARTIC ACID are dissolved in during salt-forming reaction
In water, Lomefloxacin base and L-ASPARTIC ACID is made to be reacted in water, improve reaction speed, effectively reduce and be produced into
This, economizes on resources, improves the safety coefficient in production process, avoided endangering direct labor's health, effectively reduce door
The production cost of winter propylhomoserin Lomefloxacin, promotes promoting the use of for aspartic acid laumosaren.
Specific embodiment
Below to embodiments of the present invention further instruction.
Embodiment 1
A kind of preparation method of aspartic acid laumosaren, the aspartic acid laumosaren preparation method include following
Step：A, neutralization reaction：The molar ratio for weighing lomefloxacin hydrochloride and potassium hydroxide is 1:1 lomefloxacin hydrochloride and hydrogen-oxygen
Change aqueous solutions of potassium is spare, and the water for weighing 600 times of lomefloxacin hydrochloride molal quantity is added in reaction kettle, and addition weighs spare hydrochloric acid
Lomefloxacin is stirred, and heating to 60 DEG C makes lomefloxacin hydrochloride be dissolved completely in water, starts that hydrogen-oxygen is slowly added dropwise
Change aqueous solutions of potassium, adjust the pH value of solution as 7, heat preservation carry out reaction 2 it is small when, reaction solution be cooled to often after the completion of reaction
Temperature；B, centrifugal drying material：Neutralization reaction liquid is subjected to centrifugal drying material, and is eluted using water into filtrate without chlorion, is obtained
Lomefloxacin base wet product；C, salt-forming reaction：According to 1:1:50 molar ratio weighs Lomefloxacin base, L- winter ammonia respectively
Acid, water, the water weighed, Lomefloxacin base, L-ASPARTIC ACID are sequentially added in retort, are stirred, and heating makes reaction
Tank is warming up to 95 DEG C, heat preservation carry out reaction 2 it is small when, obtain aspartic acid laumosaren crude product solution；D, decolorization filtering：Xiang Mendong
Medicinal carbon is added in propylhomoserin Lomefloxacin crude product solution, is stirred absorption 30 minutes, heat filtering press filtration filtrate enters knot
In brilliant tank；E, crystallization centrifugation：It is stirred, after being naturally cooling to 60 DEG C, logical cooling water makes temperature be reduced to 30 in crystallizing tank
Below DEG C, blowing centrifugation is carried out, filter cake is eluted using ethanol water, obtains aspartic acid laumosaren wet product and mother
Liquid；F, mother liquor refines：By mother liquor add in treatment tank in, open stirring, after being evacuated to -0.09MPa, be heated to 80 DEG C into
The mother liquor volume that row is concentrated under reduced pressure into stops concentration when reducing about 2/3, releases vacuum addition medicinal carbon, is warming up to 90 DEG C of progress
Insulated and stirred 30 minutes, heat filtering press filtration are crystallized, blowing centrifugation into crystallizing tank, filter cake are drenched with ethanol water
It washes, obtains aspartic acid laumosaren wet product；G, dries pulverizing is packed：L-aminobutanedioic acid Lome that step e and step f is obtained is husky
Star wet product is packed into baking pan, and baking pan is top-down to be encased on drying vehicle, and drying vehicle, which is pushed into heated-air circulation oven, to be dried
It is dry, 80 DEG C of oven temperature is controlled, is dried to material moisture≤3.5%, carries out cooling discharge, crush, weigh as needed,
It dispenses into complex pocket.
Alcoholic strength >=50% in the ethanol water.
The water is water of the drinking water through hyoscine made from the way of distillation.
Generally, the present invention carries out reaction and effectively reduces production cost in water, improves reaction speed, and raising produced
Security in journey has the advantages that high practical value.
Embodiment 2
A kind of preparation method of aspartic acid laumosaren, the aspartic acid laumosaren preparation method include following
Step：A, neutralization reaction：The molar ratio for weighing lomefloxacin hydrochloride and sodium hydroxide is 1:1.1 lomefloxacin hydrochloride and hydrogen
Aqueous solution of sodium oxide is spare, and the water for weighing 800 times of lomefloxacin hydrochloride molal quantity is added in reaction kettle, and addition weighs spare salt
Lomefloxacin hydrochloride is stirred, and heating to 80 DEG C makes lomefloxacin hydrochloride be dissolved completely in water, starts that hydrogen is slowly added dropwise
Aoxidize aqueous solutions of potassium, adjust the pH value of solution as 8, heat preservation carry out reaction 1 it is small when, reaction solution is cooled to after the completion of reaction
Room temperature；B, centrifugal drying material：Neutralization reaction liquid is subjected to centrifugal drying material, and is eluted using water into filtrate without chlorion, is obtained
Obtain Lomefloxacin base wet product；C, salt-forming reaction：According to 1:1:70 molar ratio weighs Lomefloxacin base, L- winter ammonia respectively
Acid, water, the water weighed, Lomefloxacin base, L-ASPARTIC ACID are sequentially added in retort, are stirred, and heating makes reaction
Tank is warming up to 60 DEG C, heat preservation carry out reaction 3 it is small when, obtain aspartic acid laumosaren crude product solution；D, decolorization filtering：Xiang Mendong
Medicinal carbon is added in propylhomoserin Lomefloxacin crude product solution, is stirred absorption 30 minutes, heat filtering press filtration filtrate enters knot
In brilliant tank；E, crystallization centrifugation：It is stirred, after being naturally cooling to 40 DEG C, logical cooling water makes temperature be reduced to 30 in crystallizing tank
Below DEG C, blowing centrifugation is carried out, filter cake is eluted using ethanol water, obtains aspartic acid laumosaren wet product and mother
Liquid；F, mother liquor refines：By mother liquor add in treatment tank in, open stirring, after being evacuated to -0.07MPa, be heated to 50 DEG C into
The mother liquor volume that row is concentrated under reduced pressure into stops concentration when reducing about 2/3, releases vacuum addition medicinal carbon, is warming up to 80 DEG C of progress
Insulated and stirred 30 minutes, heat filtering press filtration are crystallized, blowing centrifugation into crystallizing tank, filter cake are drenched with ethanol water
It washes, obtains aspartic acid laumosaren wet product；G, dries pulverizing is packed：L-aminobutanedioic acid Lome that step e and step f is obtained is husky
Star wet product is packed into baking pan, and baking pan is top-down to be encased on drying vehicle, and drying vehicle, which is pushed into heated-air circulation oven, to be dried
It is dry, 88 DEG C of oven temperature is controlled, is dried to material moisture≤3.5%, carries out cooling discharge, crush, weigh as needed,
It dispenses into complex pocket.
Alcoholic strength >=50% in the ethanol water.
The water is the water of hyoscine made from hyperfiltration.
Generally, the present invention carries out reaction and effectively reduces production cost in water, improves reaction speed, and raising produced
Security in journey improves Business Economic Benefit, has the advantages that high practical value.
Claims (4)
1. a kind of preparation method of aspartic acid laumosaren, it is characterised in that：The aspartic acid laumosaren preparation side
Method comprises the following steps：A, neutralization reaction：Weigh lomefloxacin hydrochloride and OH in alkaline aqueous solution-The molar ratio of content is 1:
1.0 ~ 1.2 lomefloxacin hydrochloride and alkaline aqueous solution are spare, the water for weighing 400 ~ 800 times of lomefloxacin hydrochloride molal quantity adds in
In reaction kettle, addition weighs spare lomefloxacin hydrochloride and is stirred, and heating to 60-90 DEG C makes lomefloxacin hydrochloride complete
Fully dissolved in water starts that alkaline aqueous solution is slowly added dropwise, and adjusts the pH value of solution as 6 ~ 8, heat preservation carry out reaction 1 ~ 2 it is small when,
Reaction solution is carried out after the completion of reaction to be cooled to room temperature；B, centrifugal drying material：Neutralization reaction liquid is subjected to centrifugal drying material, and uses water
It is eluted into filtrate without chlorion, obtains Lomefloxacin base wet product；C, salt-forming reaction：According to 1:1:50 ~ 70 mole
Than weighing Lomefloxacin base, L-ASPARTIC ACID, water respectively, the water weighed, Lomefloxacin base, L-ASPARTIC ACID are added successively
Enter in retort, be stirred, heating makes retort be warming up to 50 ~ 95 DEG C, heat preservation carry out reaction 2 ~ 4 it is small when, obtain door winter ammonia
Lomefloxacin hydrochloride crude product solution；D, decolorization filtering：Medicinal carbon is added in into aspartic acid laumosaren crude product solution, is carried out
Stirring and adsorbing 30 minutes, heat filtering press filtration filtrate enter in crystallizing tank；E, crystallization centrifugation：It is stirred, is naturally cooling to 40 ~ 60
After DEG C, cooling water is led in crystallizing tank makes temperature be reduced to less than 30 DEG C, progress blowing centrifugation, using ethanol water to filter cake
It is eluted, obtains aspartic acid laumosaren wet product and mother liquor；F, mother liquor refines：Mother liquor is added in treatment tank, unlatching is stirred
It mixes, after being evacuated to -0.1 ~ -0.07MPa, when being heated to 50 ~ 90 DEG C and be concentrated under reduced pressure into mother liquor volume and reduce about 2/3
Stop concentration, release vacuum addition medicinal carbon, be warming up to 60 ~ 90 DEG C and carry out insulated and stirred 30 minutes, heat filtering press filtration into
Crystallizing tank is crystallized, blowing centrifugation, filter cake is eluted with ethanol water, obtains aspartic acid laumosaren wet product；
G, dries pulverizing is packed：The aspartic acid laumosaren wet product that step e and step f is obtained is packed into baking pan, and baking pan is from top to bottom
Be encased on drying vehicle, drying vehicle is pushed into heated-air circulation oven and is dried, control 80 ~ 88 DEG C of oven temperature, drying
To material moisture≤3.5%, cooling discharge is carried out, crushes, weigh, dispensed into complex pocket as needed.
2. a kind of preparation method of aspartic acid laumosaren according to claim 1, it is characterised in that：The alkalescence
Aqueous solution is ammonium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, the aqueous solution of sodium acid carbonate.
3. a kind of preparation method of aspartic acid laumosaren according to claim 1, it is characterised in that：The ethyl alcohol
Alcoholic strength >=50% in aqueous solution.
4. a kind of preparation method of aspartic acid laumosaren according to claim 1, it is characterised in that：The water is
Water of the drinking water through hyoscine made from the way of distillation, ion-exchange, hyperfiltration.
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| CN201610354661.3A CN105949173B (en) | 2016-05-26 | 2016-05-26 | A kind of preparation method of aspartic acid laumosaren |
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| CN201610354661.3A CN105949173B (en) | 2016-05-26 | 2016-05-26 | A kind of preparation method of aspartic acid laumosaren |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE69106297T2 (en) * | 1990-09-28 | 1995-05-24 | Kyowa Hakko Kogyo Kk | Process for the preparation of crystals of a salt of acidic amino acid and basic amino acid. |
| CN101844995A (en) * | 2010-05-13 | 2010-09-29 | 上海李氏化学科技有限公司 | Preparation method of L-ornithine-L-aspartate |
| CN102276582A (en) * | 2011-08-10 | 2011-12-14 | 天津市汉康医药生物技术有限公司 | Lomefloxacin aspartate compound |
| CN104058981A (en) * | 2013-03-18 | 2014-09-24 | 辽宁科泰生物基因制药股份有限公司 | Preparation method of ornithine aspartate |
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Granted publication date: 20180518 Termination date: 20210526 |